This proposal will examine Drosophila models of human cognitive disorders, including neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). NFI is characterized by disfiguring tumors of the peripheral nervous system and learning defects in children with NFI. NS include features like distinct facial anomalies and congenital heart defects. A fraction of NS patients also have learning defects. NF1 is caused by mutations in a single gene NF1 while NS is genetically heterogeneous with mutations in PTPN11 accounting for 50%. This proposal will focus on role of NF1 and PTPN11 in long-term memory formation. NF1 encode GAP protein that is a negative regulator of Ras activity, whereas PTPN11 encodes a protein designated as SHP-2, a positive regulator of Ras activity. Both genes are highly conserved in fruit flies with more than 60% identical to humans. Mutations identified in patients also disrupt learning and memory in fruit flies. This proposal will utilize these clinically relevant mutations to study roles of NF1 and its regulated Ras activity in memory retrieval, and to study roles of PTPN11 and its regulated Ras activity in the spacing effect of long-term memory formation, which represent a universal property of memory formation as to that multiple training sessions with a rest interval between them (spaced training) produces stronger, longer-lasting memory than the same number of training sessions with no rest interval (massed training). I expect that new insights generated from this study will in turn facilitate development of treatment of the cognitive aspect of these disorders. This proposal includes two specific aims as outline below: 1. We will examine neuroanatomic organization of NF1-dependent memory retrieval and roles of NF1-regulated Ras activity in memory retrieval. 2. We will study PTPN11 and its regulated Ras/MAPK cascade in defining the length of resting intervals and neuroanatomical organization of PTPN11-dependent memory. PUBLIC HEALTH RELEVANCE: This proposal will examine Drosophila models of human cognitive disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Mutations in the NF1 and PTPN11 genes that cause NF1 and NS, respectively also disrupt memory formation in fruit flies. Study of these mutations will allow us gaining insights into molecular basis underlying memory retrieval and memory formation. Such understanding will in turn facilitate development of treatment for the disorders.